Skeletal muscle is terminally differentiated and as such, cannot regenerate. The cells responsible for muscle regeneration are known as satellite cells, which are normally quiescent and reside between the basement membrane and the sarcolemma of the muscle fiber. Because these cells comprise only 1-6% of the total number of muscle nuclei, little specific information is known regarding the mechanisms that regulate satellite cell function. We have recently identified two satellite cell surface receptors, syndecan-3 and syndecan-4, which are two related members of a family of 4 heparan sulfate proteoglycans that are critical regulators of satellite cell function. These proteins are comprised of a core type I integral membrane protein whose extracellular domain is decorated with heparan sulfate glycosaminoglycan (GAG) chains. Both syndecan-3 and syndecan-4 are functionally critical for satellite cells as is evident from the phenotypes of syndecan-3-/- and syndecan-4-/- mice. Satellite cells from syndecan-4 nulls appear to be generally incapable of activation and proliferation. They fail to express MyoD, myogenin and myosin heavy chain (MyHC), yet these mice appear generally normal at birth. Consistent with a satellite cell defect, muscle regeneration in these mice is severely impaired. Syndecan-3-/- mice display a strikingly different phenotype, having a large excess of myonuclei and satellite cells. Muscle sections reveal fatty and connective tissue infiltrates as well as nascent myofibers containing centrally located nuclei. It is noteworthy that null alleles for these two related and co-expressed HSPGs exhibit remarkably distinct phenotypes and appear to regulate distinct aspects of satellite cell physiology. We propose to: (i) identify the onset of the skeletal muscle phenotypes in syndecan-3-/- and syndecan-4-/- mice;(ii) functionally characterize the roles syndecan-3 and syndecan-4 play in skeletal muscle regeneration;and, (iii) identify molecular differences between wt, syndecan-3-/- and syndecan-4-/- satellite cells contributing to the observed phenotypes. These studies will provide new insights and add significant knowledge to our understanding of the regulation of muscle regeneration regulated by interactions between the satellite cell extracellular matrix and intracellular signal transduction pathways.